Identification of end phenotypes in the behavioral-variant of front temporal dementia the purpose of this proposal is to develop the expertise necessary to establish an independent lab investigating end phenotypes in young-onset neurodegenerative conditions. The behavioral-variant of fronto temporal dementia (bvFTD) is the most common clinical phenotype in front temporal lobar degeneration (FTLD) spectrum disorders. Clinically, bvFTD includes progressive decline in social conduct and executive function associated with two major classes of underlying neuropathology: inclusions composed of the microtubule-binding protein, tau (i.e. FTLD-tau), and inclusions of the RNA-binding protein, TDP-43 (i.e. FTLD- TDP). Current drug development efforts are focused on prevention of pathological tau or TDP-43 aggregation in the brain. Although 20% of cases have a pathogenic mutation resulting in FTLD-tau or FTLD-TDP, most cases are sporadic and there is currently no reliable way to detect the underlying molecular etiology in living patients, posing a significant challenge for clinical trials of these emerging therapies. The scientific goal of thi proposal is to subdivide bvFTD into screening phenotypes with biological relevance (i.e. end phenotypes) with the hypothesis that differing patterns of neuron-to-neuron spread of tau and TDP aggregations in bvFTD are associated with unique clinical and genetic features that can be detected ante mortem. Aim#1 will use a novel approach to quantify differences in regional spread of neuropathology within front temporal networks for comparative study in bvFTD with FTLD-tau vs. FTLD-TDP. Aim#2 will examine the diagnostic value of risk alleles identified in previous case-control FTLD genome-wide association studies in autopsied sporadic bvFTD, and assess their relationship to QRP map pathology burden. Aim 3 will integrate clinical and genetic markers in Aims #1 and 2 using advanced statistical techniques in patient classification to identify end phenotypes. Successful completion of these projects will have immediate utility for clinical practice and trial design for disease-modifying therapies in bvFTD. Through work on these specific aims, the structured career development plan will expand the candidate's training to include novel approaches to digital quantitative neuropathology, social cognition, neurogenesis and advanced statistical methods of patient classification under guidance from internationally-recognized leaders in the field. The proposed work will serve as the basis for a future R01 proposal studying prospective multimodal biomarker changes in these end phenotypes.